Uptake of Adriamycin in tumour and surrounding brain tissue in patients with malignant gliomas

Summary Eight patients with malignant gliomas verified on CT scan, received an intravenous injection of 50 mg of Adriamycin R, 24 hours prior to surgical removal of the tumour. Peroperatively, both tumour and surrounding tissue specimens were obtained for determination of the tissue concentrations of Adriamycin and its reduced metabolite Adriamycinol. It was found that Adriamycin could be detected in tumour tissue from all patients. The concentration varied between 0,9 and 4,6 nmol/g tissue. In contrast, Adriamycin could only be detected in surrounding brain tissue from one patient.In anin vitro study a human malignant glioma cell line (U-251 MG) was exposed to various concentrations of Adriamycin for 24 hours. It was found that an intracellular drug concentration above 30 nmol/g cells caused a concentration dependent inhibition of cell growth. Thus, it is likely that the poor effect of Adriamycin on patients with malignant gliomas is due to an ineffective drug accumulation in the tumour tissue.     

Secretion of cathepsin B by human gliomas in vitro

There is evidence from investigations of non-CNS neoplasms that secreted proteolytic enzymes may facilitate tumour invasion by partially degrading extracellular matrix (ECM). Among the enzymes which may be involved are members of the cysteine proteinase superfamily and especially cathepsin B (CB). In the present investigation we have studied CB in human gliomas in vitro , concentrating particularly on CB secretion, as extracellular enzyme is of prime importance in this context. We have found that CB is secreted by gliomas in vitro as a latent zymogen, requiring activation. This has been confirmed by gel chromatography which indicated that CB is secreted as a 42 kDa proenzyme which may be proteolytically processed to an enzymatically active 29 kDa molecule. The inactive, high molecular weight, latent CB is stable at extracellular pH in contrast to the activated low molecular weight form which rapidly loses activity at this pH. We have also measured secretion of cysteine proteinase inhibitors (CPI), as their presence would have a direct influence on the effective activity of CB, and found that all of the gliomas secreted significant amounts of a CPI as assessed by papain inhibition. Our experiments suggest that a number of factors are involved in the regulation of extracellular glioma-derived CB activity. These include: rate of secretion of pro-CB, rate of CB activation, destabilization of CB at neutral pH and the presence of cysteine proteinase inhibitors.     

Localized proton spectroscopy of inoperable brain gliomas. Response to radiation therapy

Within vivo 1H-MRS resonances of several metabolites were simultaneously measured in cerebral gliomas and adjacent normal brain. 15 patients with inoperable brain gliomas all histologically verified were monitored with 1H-MRS and MRI before and after radiotherapy. 11 patients were evaluable. 1H-MRS technique evolved from single volume measurements to one dimensional and two dimensional 1H spectroscopic imaging. In all patients N-acetyl-aspartate signals were decreased in tumour areas compared to the normal brain hemisphere. No recovery was seen after radiotherapy. Choline signals were increased in tumour margins of high grade gliomas and more diffusely in low grade gliomas. In 5 patients the choline resonance decreased after radiotherapy, accompanied by a shrinkage of tumour diameter on MRI. Lactate signals were present in high grade and unspecified astrocytomas and absent in most low grade gliomas. In 3 patients the lactate signal disappeared after radiotherapy. These observations indicate the feasibility of 1H-MRS in monitoring metabolic responses on radiotherapy of brain gliomas.     

Spontaneous regression of optic pathways gliomas in three patients with neurofibromatosis type I and critical review of the literature

Case reports The authors report their experience about three children (two girls, one boy; average age 1.6 years) with a spontaneous regression of optic gliomas. All of them had a previous diagnosis of neurofibromatosis type 1 (NF 1). None of them underwent surgery or biopsy nor received chemotherapy or radiotherapy. The complete regression was documented by MRI scans performed during a mean follow-up of 6.3 years.Literature review Moreover, the authors analyze the features of the 16 cases previously reported in English literature of spontaneously regressed optic gliomas with an overview of the different therapeutic strategies. The knowledge that this kind of tumor, particularly in young patients, may regress is important in the decision of the best therapeutic approach.     

Ultrastructural study of micro-blood vessels in human brain tumors and peritumoral tissue

Summary Ultrastructural and tracer studies have demonstrated that vasogenic edema, a serious complication of brain tumor is the result of increased permeability of tumor vessels. However, not much information is available on the alterations in the vessels in the peritumoral areas. Therefore, we studied the ultrastructural changes in the tumor micro-blood vessels (MBVs) in 20 cases of glioma and compared these with the changes in the peritumoral MBVs in 10 of these cases.The tumor MBVs showed remarkable structural changes, viz, increase in pinocytotic vesicles, large vacuoles and microvilli in the endothelial cells, varying degrees of endothelial attenuation and fenestration, an occasional partially or completely opened-up junction and some pale and edematous endothelial cells, which can adequately explain their increased permeability.The peritumoral MBVs also showed evidence of increased permeability in the form of increased pinocytotic vesicles, large vacuoles and microvilli associated with pale and edematous cytoplasm of some endothelial cells. Thickened multilayered basement membrane, absence of ensheathment of capillary basement membrane by astrocytic cell processes and widened perivascular space were observed in both tumoral and peritumoral MBVs.An interesting observation was that in the peritumoral MBVs, the pinocytotic vesicles were most conspicuously seen on the abluminal side of the endothelial cells often fused with the abluminal plasma membrane. Although a static study like this cannot indicate any definite direction of movement of fluid, we feel that the occurrence of reverse pinocytosis is a distinct possibility in the peritumoral MBVs and that it may be an important means of resorption of edema fluid.     

Effects of epidermal growth factor in the mammalian central nervous system: Its possible implications in brain pathologies and therapeutic applications

The development and maintenance of the normal functional integrity of the mammalian central nervous system is under the influence of a number of growth and trophic factors. One such growth factor, epidermal growth factor, has been detected in the mammalian brain and found to be associated with various brain regions and cell types. This small ubiquitous polypeptide can influence the proliferation, Metabolism, and differentiation of both glia and neurons in the central nervous system. We discuss the effects of epidermal growth factor on glial and neuronal cell function in an attempt to understand its role in development and maintenance of normal brain integrity. In addition, we review its possible implications in several pathological states in the central nervous system and speculate on therapeutic applications for this growth factor. © 1992 Wiley-Liss, Inc.     

Surgery of giant gliomas of chiasma and IIIrd ventricle

Summary During a period of 17 years (from 1976 till now) 45 patients with giant gliomas of the chiasma and the IIIrd ventricle out of a total amount of 120 patients with hypothalamic gliomas were operated. The following classification of tumours was used: I) tumours with predominant anterior growth; II) tumours which infiltrate chiasma and penetrate into the IIIrd ventricle; III) gliomas of the floor of the IIIrd ventricle and the chiasma, growing into the ventricle cavity; IV) tumours of the chiasma, optic tract and thalamus. The authors come to the conclusion, that surgical removal of giant tumours of the chiasma and the IIIrd ventricle, though risky, may result in an improvement or stabilisation of visual functions (77%) and a long period free from recurrencies (9.5%). The postoperative period is relatively favourable and the mortality is low (6%). The main contraindication in our opinion is a wide infiltration of adjacent brain structures by the tumour and spreading along both optical tracts. We consider the giant size of a tumour in itself a sufficient indication for surgery.     

MMP-2、TIMP-2在脑胶质瘤中的表达及其意义

目的 分析MMP-2、TIMP-2的表达与脑胶质瘤恶性程度和侵袭性之间的关系。方法 采用免疫组化和原位杂交的方法,检测42例人脑胶质瘤和8例正常脑组织中,MMP-2 mRNA、MMP-2和TIMP-2蛋白表达。结果 MMP-2蛋白表达水平(LI)与肿瘤的分级呈正相关(r=0.872,P<0.01);Ⅲ、Ⅳ级与正常脑组织、Ⅰ～Ⅱ级之间均有显著的差异(P<0.01)。MMP-2mRNA表达与肿瘤的分级同样呈正相关(P<0.01);Ⅲ、Ⅳ级与正常脑组织、Ⅰ～Ⅱ级之间均有显著的差异(P<0.01)。MMP-2蛋白表达增高时TIMP-2蛋白表达也增高;但随着肿瘤恶性程度的增加,TIMP-2表达强度增加的幅度较MMP-2明显减缓。结论 MMP-2的高表达与脑胶质瘤恶性程度呈正相关;TIMP-2与MMP-2间的平衡失调与脑胶质瘤的侵袭性和恶性程度密切相关。     

Growth effects of epidermal growth factor (EGF) and a monoclonal antibody against the EGF receptor on four glioma cell lines

Summary Epidermal growth factor (EGF) has been shown to stimulate DNA synthesis and cell division in normal glia. At least half of malignant human gliomas (MHG) express high levels of the EGF receptor (EGFR), which are above those detected in normal brain. The demonstration that antibodies against the EGFR inhibit the growth of squamous cell carcinoma line A-431, with large numbers of EGFR, in vitro and in vivo raises the possibility that these agents could be used therapeutically against malignant human gliomas either alone or conjugated to other agents. We have measured the growth effects of EGF and an anti-EGFR monoclonal antibody, 528 (Ab-528), on four well-characterized human malignant glioma cell lines, D-263 MG, D-247 MG, U-343 MGa Cl 26, and D-37 MG, with 2.9×10⁴, 1.5×10⁵, 8.6×10⁵ and 1.59×10⁶ EGFRs per cell, respectively. EGF significantly increased cell number in D-263 MG and D-37 MG by 65% and 74%, respectively, had no effect on D-247 MG, and significantly decreased cell number in U-343 MGa Cl 26 by 39%. U-343 MGa Cl 26 growth was inhibited 19% by Ab-528, but Ab-528 had no effect on growth of the other MHG lines. Ab-528 significantly inhibited all EGF-mediated growth effects. These studies demonstrate that, although Ab-528 alone has little antiproliferative activity on MGH, it successfully competes with EGF to reduce the biological effects of EGF-EGFR binding. Therefore, this antibody could potentially be used to target radioisotopes to MHG via the EGFR for diagnosis and therapy.Supported by Grants CA-11898, NS-20023, CA-43722, and the Association for Brain Tumor Research (MHW, PAH)